ABSTRACT

Context Warfarin has been shown to be highly efficacious for preventing thromboembolism
in atrial fibrillation in randomized trials, but its effectiveness and safety
in clinical practice is less clear.

Objective To evaluate the effect of warfarin on risk of thromboembolism, hemorrhage,
and death in atrial fibrillation within a usual care setting.

Design Cohort study assembled between July 1, 1996, and December 31, 1997,
and followed up through August 31, 1999.

Setting Large integrated health care system in Northern California.

Patients Of 13 559 adults with nonvalvular atrial fibrillation, 11 526
were studied, 43% of whom were women, mean age 71 years, with no known contraindications
to anticoagulation at baseline.

Main Outcomes Ischemic stroke, peripheral embolism, hemorrhage, and death according
to warfarin use and comorbidity status, as determined by automated databases,
review of medical records, and state mortality files.

Results Among 11 526 patients, 397 incident thromboembolic events (372
ischemic strokes, 25 peripheral embolism) occurred during 25 341 person-years
of follow-up, and warfarin therapy was associated with a 51% (95% confidence
interval [CI], 39%-60%) lower risk of thromboembolism compared with no warfarin
therapy (either no antithrombotic therapy or aspirin) after adjusting for
potential confounders and likelihood of receiving warfarin. Warfarin was effective
in reducing thromboembolic risk in the presence or absence of risk factors
for stroke. A nested case-control analysis estimated a 64% reduction in odds
of thromboembolism with warfarin compared with no antithrombotic therapy.
Warfarin was also associated with a reduced risk of all-cause mortality (adjusted
hazard ratio, 0.69; 95% CI, 0.61-0.77). Intracranial hemorrhage was uncommon,
but the rate was moderately higher among those taking vs those not taking
warfarin (0.46 vs 0.23 per 100 person-years, respectively; P = .003, adjusted hazard ratio, 1.97; 95% CI, 1.24-3.13). However,
warfarin therapy was not associated with an increased adjusted risk of nonintracranial
major hemorrhage. The effects of warfarin were similar when patients with
contraindications at baseline were analyzed separately or combined with those
without contraindications (total cohort of 13 559).

Conclusions Warfarin is very effective for preventing ischemic stroke in patients
with atrial fibrillation in clinical practice while the absolute increase
in the risk of intracranial hemorrhage is small. Results of randomized trials
of anticoagulation translate well into clinical care for patients with atrial
fibrillation.

Figures in this Article

Multiple randomized trials have demonstrated warfarin therapy to be
highly efficacious in reducing risk of ischemic stroke and other systemic
thromboembolism in patients with atrial fibrillation, with relatively low
rates of bleeding.1- 5 Aspirin
has substantially less efficacy, particularly among patients at moderate to
high risk of stroke.2,3,6 However,
concerns persist about the effectiveness and safety of anticoagulation with
warfarin in persons treated in usual clinical care because the randomized
trials enrolled highly selected patients, included few very elderly patients,
and closely monitored anticoagulation. This has important clinical implications
because atrial fibrillation occurs commonly, particularly among the elderly,7 and because the potential benefits vs risks of warfarin
therapy are dependent on good control of anticoagulation intensity within
a relatively narrow international normalized ratio (INR) range.8- 10

Previous studies of thromboembolic and hemorrhagic outcomes of antithrombotic
therapy for patients with atrial fibrillation treated in clinical practice
settings have been relatively small, limited in clinical detail, or lacked
information on longitudinal exposure to anticoagulation.11- 18 As
a result, it remains unclear how well randomized trials of anticoagulation
apply to the broader spectrum of patients with atrial fibrillation in typical
clinical settings. To address these issues, we systematically examined the
effects of warfarin therapy on the risk of ischemic stroke and other systemic
thromboembolism, intracranial and other hemorrhage, and all-cause mortality
focusing specifically on follow-up of 11 526 adults with nonvalvular
atrial fibrillation who did not have contraindications to warfarin therapy
at study entry within the Anticoagulation and Risk Factors In Atrial Fibrillation
(ATRIA) Study19 cohort (N = 13 559).

METHODS

Study Population

Assembly of the ATRIA cohort has been described in detail previously.19 Briefly, we identified all patients 18 years or older
with diagnosed atrial fibrillation within Kaiser Permanente of Northern California
based on physician-assigned diagnoses of atrial fibrillation found in ambulatory
visit (International Classification of Diseases, Ninth Revision [ICD-9] code 427.31) and electrocardiographic
databases between July 1, 1996, and December 31, 1997. Patients were included
if they had serial outpatient diagnoses of atrial fibrillation, with the large
majority having electrocardiographic evidence of atrial fibrillation.19 We excluded patients with diagnosed mitral stenosis,
previous valvular repair or replacement, transient perioperative atrial fibrillation,
or recent hyperthyroidism in order to include only patients with nonvalvular
atrial fibrillation that was presumably not transient or due to a reversible
cause.19

Patient Characteristics

We searched clinical inpatient and ambulatory visit (outpatient clinic
and emergency department) databases during the 5 years before the first outpatient
atrial fibrillation diagnosis during the study period (index date) to identify
previously diagnosed ischemic stroke, heart failure, coronary heart disease,
and hypertension using relevant ICD-9 codes.7,19 We used a validated, comprehensive
health plan diabetes registry to identify patients with diabetes mellitus.7,19 We obtained information from clinical
inpatient and ambulatory-visit databases for the following potential contraindications
to warfarin therapy: previous intracranial, gastrointestinal, and other bleeding;
prior cirrhosis, hepatitis, or seizure disorder; prior mechanical fall; and
diagnosed dementia.19 Information from medical
care received at both health plan and non–health plan facilities was
obtained through these databases.

Warfarin Exposure and Anticoagulation Intensity

Warfarin use was determined using a combination of information from
prescriptions and INR measurements found in health plan pharmacy and laboratory
databases, respectively. Longitudinal warfarin exposure was based on number
of days of supply per prescription and intervening INRs. For any 2 consecutive
prescriptions with a gap of up to 60 days, a patient was considered continually
taking warfarin. For gaps longer than 60 days, we considered the patient continually
taking warfarin if there were intervening INR measurements at least every
42 days. Otherwise, the patient was considered not taking warfarin from day
31 after the end date of the first prescription until the start date of the
next prescription. This grace period of 30 days at the end of each warfarin
period was given since changes in warfarin dosages are common. We validated
the utility of this approach by comparing the anticoagulation status from
the computerized algorithm with warfarin status documented in the medical
record at the time of an outcome event for 1207 patients who experienced thromboembolism
or hemorrhage during follow-up using chart review (κ = 0.84).20

Of note, use of non–health plan pharmacies for warfarin was low
(<6%) in this cohort,19 and approximately
80% of patients receiving warfarin were managed in pharmacist- or nurse-led
anticoagulation clinics. Time spent in different INR levels was calculated
using interpolation methods similar to those of Rosendaal et al,21 with
gaps between INR tests greater than 8 weeks excluded.

Thromboembolic Events During Follow-up

From the index date through August 31, 1999, we prospectively searched
hospitalization and billing claims databases for discharge diagnoses indicating
potential thromboembolic and outcome events. A total of 783 potential thromboembolic
events were individually adjudicated by medical records review. (ICD-9 codes used for primary discharge diagnoses indicating ischemic
stroke and peripheral embolism are available upon request.) We excluded nonfatal
hospitalizations with ICD-9 codes 433, 434, or 436.0
lasting less than 48 hours that were accompanied by carotid endarterectomy
because chart review demonstrated that the overwhelming majority of these
episodes were not acute strokes.

Medical records from all potential events were reviewed by a 3-physician
clinical outcomes committee. If consensus was not reached, a final decision
was made by a consulting neurologist. A valid ischemic stroke was defined
as a documented acute neurological deficit lasting more than 24 hours that
was not explained by other etiologies (eg, primary hemorrhage, trauma, infection,
or vasculitis). A valid peripheral embolism was defined as an embolus identified
by radiographic imaging, intraoperative examination, or pathological findings
in the absence of underlying atherosclerotic disease in the affected artery.
We reviewed a random sample of 35 admissions with only a secondary discharge
diagnosis of ischemic stroke; only 11.4% had a validated stroke. Thus, we
did not adjudicate admissions with only a secondary discharge diagnosis of
ischemic stroke because only an estimated 24 additional strokes would have
been added overall.

Nested Case-Control Study

Because data on longitudinal aspirin use were not available from pharmacy
databases and because aspirin has some efficacy for stroke prevention,6 we further refined our estimate of the effectiveness
of warfarin vs no antithrombotic therapy by conducting a nested case-control
analysis of antithrombotic therapy and systemic thromboembolism.22,23 This
analysis included a sample of 294 cohort members with incident systemic thromboembolism
during follow-up and 294 control patients who were matched to case patients
for follow-up time in the cohort24 and who
had 1 or more outpatient clinic visits within 3 months before or after the
matching case's event date. None of the case or control patients had a contraindication
to anticoagulation at baseline. We reviewed automated databases and inpatient
medical records for cases to determine the use of antithrombotic therapy (warfarin,
aspirin, or no antithrombotic therapy). Among controls, we reviewed all available
outpatient clinic medical records for antithrombotic therapy status during
the 3 months before and after the matching case date if no evidence of warfarin
exposure was found using our automated warfarin algorithm described above.
A patient with mention of aspirin use in any clinic record during this period
was considered an aspirin user.

Hemorrhagic Events During Follow-up

We searched hospitalization and billing claims databases for primary
and secondary discharge diagnoses of intracranial hemorrhage, and primary
discharge diagnoses for gastrointestinal and other nonintracranial hemorrhage.
Intracranial hemorrhage associated with concomitant discharge diagnosis of
major trauma (ICD-9 codes
852.1, 852.3, 852.5, and 853.1) was excluded. (ICD-9 codes
for discharge dignoses indicating intracranial, gastrointestinal, and other
hemorrhage are available upon request.) Hemorrhagic events not leading to
hospitalization or death were excluded. We adjudicated 659 potential hemorrhagic
events using a similar approach as described above for thromboembolism. Major
hemorrhage other than intracranial hemorrhage was defined as fatal, requiring
2 or more units of transfused blood or occurring in a critical anatomic location
(eg, ocular hemorrhage impairing vision or retroperitoneal hematoma). In addition,
medical records review of a random sample of 110 hospitalizations with secondary
discharge diagnoses of hemorrhage (excluding intracranial) showed that 32.7%
of these events were valid hemorrhages, but only 13.6% of these were major
hemorrhages, so we did not include this approach in our search strategy. We
estimate these excluded events would have added an absolute 0.48% to our aggregate
annual rate of nonintracranial hemorrhage with a negligible addition to the
rate of major hemorrhage.

Mortality and Disenrollment

All-cause mortality through August 31, 1999, was ascertained from hospital
databases, health plan member reporting, and the comprehensive California
state death certificate registry.25 Membership
gaps of more than 90 days without evidence of interim ambulatory care was
considered disenrollment from the health plan, and patients were censored
at the last known membership date.

Statistical Analyses

The entire ATRIA cohort included 13 559 patients. The primary focus
of our report is on the 11 526 cohort members with no known contraindications
to warfarin at entry to the study.

Continuous variables are provided as mean (SDs), with comparisons between
baseline warfarin users and nonusers using the t test.
Categorical variables are reported as proportions with comparisons between
baseline warfarin users and nonusers using χ2 test. Crude event
rates were calculated using log-linear (Poisson regression) models with a
generalized estimating equations approach to account for the same patients'
contributing person-years taking and not taking warfarin and are given as
events per 100 person-years with 95% confidence intervals (CIs).26 We
excluded 52 validated events (47 ischemic strokes and 5 other thromboembolism)
that occurred on the index date because it was unclear whether the atrial
fibrillation diagnosis preceded the outcome event. Event rates for thromboembolism
during periods of taking and not taking warfarin are given in the presence
or absence of known risk factors for stroke, as well as by the CHADS2 score, a recently proposed stroke risk stratification scheme for atrial
fibrillation. The CHADS2 index measures stroke risk by assigning
1 point each for congestive heart failure, hypertension, age 75 years or older,
and diabetes mellitus, with 2 points added for patients who have a history
of stroke or transient ischemic attack.27

To evaluate the effectiveness of warfarin compared with no warfarin
therapy for prevention of thromboembolism, Kaplan-Meier survival curves were
constructed, and multivariable Cox proportional hazard models were performed
that incorporated time-dependent information on warfarin use, as well as demographic
characteristics and known risk factors for stroke identified during follow-up.28,29

We additionally used propensity score techniques30 modified
for time-dependent survival analyses in an attempt to further reduce confounding
by indication for warfarin. Using this method, each patient's predicted likelihood
of receiving warfarin therapy was assigned daily throughout the follow-up
period and incorporated into regression models as a continuous time-dependent
covariate. For all analyses of the 11 526 patients without contraindications
to warfarin at baseline, patients were censored if they had acquired a new
relative or absolute contraindication to anticoagulation because they were
no longer considered eligible to receive warfarin therapy. In analyses of
the entire cohort of 13 559 patients, there was no censoring because
of their having developed a contraindication to warfarin therapy during follow-up,
and propensity score methods included terms both for risk factors for stroke
and for contraindications. Patients in our cohort considered not taking warfarin
could either be taking aspirin or no antithrombotic therapy. We examined the
relative effectiveness of warfarin compared with no antithrombotic therapy
through our nested case-control study using multivariable conditional logistic
regression.31 We used similar proportional
hazard model approaches as described above to evaluate the safety of anticoagulation
for the outcomes of intracranial hemorrhage and nonintracranial major hemorrhage.
Finally, to examine the association between warfarin therapy and all-cause
mortality, we performed proportional hazard regression adjusting for age,
sex, known risk factors for stroke, and time-dependent propensity to receive
warfarin.

A 2-tailed P value less than .05 was considered
statistically significant. All analyses were conducted using SAS statistical
software version 8.2 (SAS Institute Inc, Cary, NC). This study was approved
by institutional review boards of the collaborating institutions.

RESULTS

Baseline Characteristics and Follow-up

Among 11 526 adults with nonvalvular atrial fibrillation and no
known contraindications to anticoagulation at baseline, 43% were women and
were a mean age of 71 years (Table 1).
More than 75% of the cohort was aged 65 years or older. Eight percent of the
cohort had a prior ischemic stroke, 28.5% had diagnosed heart failure, 50.1%
had diagnosed hypertension, 16.8% had diabetes mellitus, and 27.7% had known
coronary disease. Overall, those receiving warfarin at baseline were more
likely to be men and have had a prior ischemic stroke, diagnosed heart failure,
diagnosed hypertension, diabetes mellitus, and coronary heart disease (Table 1).

Warfarin Therapy and Outcome Events

During follow-up, there were 12 958 person-years of warfarin exposure
among 7445 patients. The proportion of time spent in each INR range during
follow-up was INR less than 1.5 (4.2%); INR, 1.5-1.9 (22.6%); INR, 2.0-3.0
(62.5%); and INR more than 3.0 (10.7%) based on more than 210 000 INRs
performed during eligible periods while taking warfarin. The INR interpolation
was not performed for 18% of the period during which patients were considered
to be taking warfarin because of gaps between INR tests that exceeded 8 weeks.

There were 148 thromboembolic events (141 ischemic strokes, 7 other
thromboembolism) that occurred among the patients receiving warfarin therapy
(1.17 per 100 person-years; 95% CI, 1.00-1.38) compared with 249 events (231
ischemic strokes, 18 other thromboembolism) among patients not receiving warfarin
(2.03 per 100 person-years, 95% CI, 1.79-2.30; P<.001; Table 2, Figure 1). Of 141 strokes that occurred among those taking warfarin,
4 had no INR available at presentation, and 87 (63.5%) of the remaining 137
had INR of less than 2.0. Thromboembolic event rates among those not taking
warfarin were significantly higher for patients with risk factors for stroke,
including prior stroke, diabetes, hypertension, diagnosed heart failure, coronary
heart disease, and age 75 years or older, but the rates were substantially
lower for those taking warfarin in these subgroups (Table 3). Lower rates of thromboembolism were also observed among
patients taking warfarin at each level of the CHADS2 score (Table 3).

There were 88 patients with intracranial hemorrhagic and 267 non–intracranial
hemorrhagic events leading to hospitalization (237 gastrointestinal and 30
other sites) during follow-up (Table 2).
Among 267 nonintracranial hemorrhages, 139 (52.0%) met criteria for major
bleeding. The crude absolute rate of intracranial hemorrhage was only moderately
higher among those taking vs those not taking warfarin although there were
no significant differences in the rates of gastrointestinal hemorrhage or
other hemorrhage (Table 2).

Multivariable Analysis of Warfarin

Effect on Thromboembolism. Using proportional
hazards models that adjusted for time-dependent confounders (demographic characteristics
and stroke risk factors) and the likelihood of receiving warfarin over time,
we found that warfarin therapy was associated with a reduced thromboembolic
risk, adjusted hazard ratio (HR) 0.49 (95% CI, 0.40-0.61), compared with no
warfarin therapy.

Using a nested case-control design, we further refined the effect of
warfarin compared with no antithrombotic therapy by taking into account the
use of aspirin among patients considered not taking warfarin. After adjustment
for potential confounders, warfarin was associated with an adjusted relative
odds of thromboembolism of 0.36 (95% CI, 0.22-0.58) compared with no antithrombotic
therapy, and an adjusted relative odds of 0.42 (95% CI, 0.25-0.71) compared
with aspirin.

Effect on Bleeding. Warfarin was associated
with a nearly 2-fold adjusted increased risk of intracranial hemorrhage (adjusted
HR, 1.97; 95% CI, 1.24-3.13) compared with no warfarin therapy although there
was no significant association between warfarin use and nonintracranial major
hemorrhage (adjusted HR, 0.84; 95% CI, 0.59-1.18), after adjusting for potential
confounders (Table 2).

Effect on All-Cause Mortality. There were 1235
deaths during follow-up among patients without a known baseline contraindication
to warfarin, with a lower rate of death among patients taking (4.46 per 100
person-years) vs patients not taking warfarin (5.33 per 100 person-years, P = .002). Warfarin use was associated with a 31% reduction
in the risk of all-cause mortality (adjusted HR, 0.69; 95% CI; 0.61-0.77),
after adjusting for differences in age, sex, known risk factors for stroke,
and time-dependent likelihood of receiving warfarin.

Outcomes and Warfarin Use in Patients With Contraindications and in
Entire Cohort

Among the 2033 subjects excluded from the main analyses above because
of the presence of relative or absolute contraindications to warfarin therapy,
43.6% were prescribed warfarin at index date. These patients were older with
a mean (SD) age of 75.6 (10.1) years and had a higher prevalence of risk factors
for stroke at baseline than the 11 526 patients without contraindications
to warfarin therapy (ie, 16.8% prior stroke, 42.6% diagnosed heart failure,
55.7% diagnosed hypertension, 20.0% diabetes mellitus, and 36.1% coronary
heart disease). Thirty-seven thromboembolic events (32 ischemic strokes, 5
other thromboembolism) occurred among those taking warfarin (2.20 per 100
person-years; 95% CI, 1.59-3.03) compared with 109 thromboembolic events (104
ischemic strokes, 5 other thromboembolism) among those not taking warfarin
(4.39 per 100 person-years; 95% CI, 3.64-5.31; P<.001)
in this subgroup. After adjusting for potential confounders and the propensity
to receive warfarin, warfarin therapy was associated with a 48% (95% CI, 24%-65%)
decreased rate of thromboembolism.

The results for the entire cohort of 13 559 members, regardless
of the presence of contraindications to warfarin therapy at baseline, were
very similar to the stratified results shown above, except for modestly higher
event rates that were in part due to patients' not being censored after the
development of a contraindication to anticoagulation during follow-up. There
were 204 thromboembolic events (190 ischemic strokes, 14 other thromboembolism)
that occurred among patients taking warfarin (1.36 per 100 person-years; 95%
CI, 1.19-1.56) compared with 394 events (369 ischemic strokes, 25 other thromboembolism)
among those not taking warfarin (2.54 per 100 person-years; 95% CI, 2.30-2.81; P<.001). Using proportional hazards models that adjusted
for time-dependent confounders (demographic characteristics, stroke risk factors,
and potential contraindications to anticoagulation) and likelihood of receiving
warfarin, warfarin therapy was associated with a reduced thromboembolic risk
compared with no warfarin therapy (adjusted HR, 0.51; 95% CI, 0.43-0.61).
The rates of intracranial hemorrhage were 0.51 (95% CI, 0.41-0.63) per 100
person-years among those taking vs 0.33 (95% CI, 0.25-0.43) among those not
taking warfarin (adjusted HR, 1.57; 95% CI, 1.10-2.26).

COMMENT

Within a large ambulatory cohort of patients with nonvalvular atrial
fibrillation in clinical practice who appeared eligible for anticoagulation,
warfarin reduced the risk of ischemic stroke and peripheral embolism by 51%
compared with no warfarin therapy. Our nested case-control analysis indicated
this effect was even larger when compared with those taking neither aspirin
nor warfarin. Warfarin reduced the risk of thromboembolism across known stroke
risk factors in atrial fibrillation. Nearly two thirds of individuals sustaining
an ischemic stroke while taking warfarin had an INR of less than 2.0, suggesting
even greater benefit of anticoagulation, if maintained in the recommended
range (INR, 2.0-3.0).10,32 Anticoagulation
was associated with nearly a doubling in the relative rate of intracranial
hemorrhage, but the additional absolute risk of intracranial hemorrhage on
anticoagulation was low. We also observed no significant increase in the rate
of nonintracranial major hemorrhage on warfarin, likely reflecting preferential
exclusion of patients at high risk for such bleeding. Finally, we observed
a favorable association between warfarin use and all-cause mortality. These
effects were also observed among the 2033 cohort members excluded from our
main analyses because of mostly relative contraindications to warfarin therapy
at baseline.

Our results are consistent with previous clinical trials of anticoagulation
for atrial fibrillation and are particularly relevant given recent results
from the Atrial Fibrillation Follow-up Investigation of Rhythm Management
(AFFIRM)33 and Rate Control vs Electrical Cardioversion
for Persistent Atrial Fibrillation (RACE)34 trials,
which highlight the importance of long-term anticoagulation in patients with
atrial fibrillation even after normal sinus rhythm is reestablished. The pooled
intention-to-treat analysis of the first 5 primary prevention trials and a
secondary prevention trial demonstrated that warfarin reduces the risk of
stroke by two thirds35 while aspirin was much
less efficacious.36

There have been concerns that the dramatic results from these trials
might not translate directly to typical clinical practice. Patients enrolled
in the trials were highly selected (eg, <10% of those screened in the Stroke
Prevention in Atrial Fibrillation [SPAF] study were enrolled37),
few very elderly patients participated, and the high quality of anticoagulation
management in the trials might not be duplicated in clinical settings. Previous
studies of antithrombotic therapy in atrial fibrillation outside of trials
have primarily studied selected patient populations (eg, hospitalized or nursing
home patients with atrial fibrillation), involved relatively modest sample
sizes, had small numbers of outcome events leading to less precise estimates
of effect, or other methodological limitations.12- 14,16- 18,38- 40

Our results materially extend these prior findings by providing contemporary
and precise estimates of thromboembolism and hemorrhage rates in a broad population
of individuals with atrial fibrillation, along with more complete adjustment
for potential confounders and attempts to control for the likelihood of receiving
warfarin over time. Our observed stroke rates were somewhat lower than what
most prior studies had reported. In part, this lower risk may have been due
to the ambulatory nature of our cohort and its inclusion of more low-risk
younger patients than previous studies.41,42 In
addition, the lower stroke rate may also reflect our use of validated stroke
as an end point rather than the combination of stroke and transient ischemic
attack or the use of claims data diagnoses alone. Analysis of the experience
of the entire ATRIA cohort, including both patients with and without contraindications
to warfarin therapy at baseline or during follow-up, resulted in a modestly
higher rate of thromboembolism of 2.54 per 100 person-years. Of note, a recently
reported study from the Framingham Heart Study also observed somewhat lower
rates of ischemic stroke among patients with presumed new-onset atrial fibrillation.43 Regardless, the beneficial impact of warfarin therapy
on thromboembolic risk was confirmed.

Similar to the pooled analyses of randomized trials,35 we
also observed a favorable association of warfarin therapy and risk of all-cause
mortality although these results should be interpreted cautiously given that
we were unable to adjust for all known predictors of death. In addition, our
relatively low absolute rate of intracranial hemorrhage among those taking
warfarin was consistent with previous trials and observational studies, suggesting
that anticoagulation can be safely administered in clinical practice for the
generally older patients with atrial fibrillation.

This is the largest individual prospective study of atrial fibrillation
to date and included substantially more thromboembolic and hemorrhagic outcomes
than reports of pooled results of the clinical trials of antithrombotic therapy
or of observational studies.6 Our cohort is
an ambulatory population of patients from a real world setting and has greater
age, sex, and racial diversity7 than populations
in the clinical trials. For example, in comparing a pooled analysis of 5 randomized
controlled trials,35 our study included a greater
proportion of elderly patients (mean age 71 vs 69 years; 23% vs 10% age ≥80
years, respectively) and women (43% vs 27%, respectively). There was also
a higher prevalence of stroke risk factors and comorbid conditions in our
cohort compared with trial populations, reflecting the broader spectrum of
patients with atrial fibrillation seen in clinical practice. We used several
complementary methods to identify clinically significant thromboembolic and
hemorrhagic events and validated these outcomes through physician-based review
of medical records using standardized criteria rather than administrative
claims alone or patient self-report. In addition, longitudinal warfarin exposure
was obtained using both comprehensive pharmacy and laboratory databases.

Our study also had several limitations. As a study of outcomes in clinical
practice, our design is necessarily observational. There may still be residual
treatment selection bias in our estimates of warfarin's impact despite censoring
patients with a known relative or absolute contraindication to anticoagulation
at baseline or during follow-up and additional accounting for risk factors
before and after index date. We previously demonstrated the utility of our
use of automated databases to identify stroke risk factors compared with chart
review.19 However, any residual confounding
by indication would have likely led to our underestimating warfarin's effectiveness
in reducing ischemic stroke.30 The similar
crude rate of nonintracranial bleeding observed in patients taking or not
taking warfarin suggests that we may not have completely identified all contraindications
to anticoagulation (ie, residual confounding by contraindication).44 Patient features, other than age, that predispose
to intracranial hemorrhage are not well established, thereby minimizing the
potential for residual confounding by contraindication in our estimate of
warfarin's effect on this most feared type of bleeding.

We did not have information on aspirin use among all patients not prescribed
warfarin, but our nested case-control study allowed an estimate of warfarin's
effect compared with those taking neither warfarin nor aspirin. We also did
not attempt to further characterize stroke subtype although the majority of
atrial fibrillation–related strokes are considered embolic.45 Although our study population has previously been
shown to be representative of the surrounding northern California and statewide
population,46 our results may not be completely
generalizable to uninsured populations, other geographic regions, or other
health care settings. For example, within our health care setting, many of
the patients receiving warfarin were followed up in specialized anticoagulation
clinics that likely contributed to achieving 63% of the time in the therapeutic
INR range (2.0-3.0), which was similar to the level of control seen in certain
trials (eg, SPAF III3).

We may have missed a small number of thromboembolic or hemorrhagic events
that did not lead to hospitalization or death; but given our comprehensive
approach to capturing hospitalizations and deaths, we estimate that the likelihood
of missed serious events was low and not differentially distributed by treatment
status.

In conclusion, we found that warfarin appears to be very effective in
usual clinical practice for stroke prevention in patients with nonvalvular
atrial fibrillation and only marginally increases the absolute risk of intracranial
hemorrhage. Overall, our results demonstrate that findings of the randomized
trials of anticoagulation for atrial fibrillation translate well into clinical
practice. Our study adds further support for the routine use of anticoagulation
for eligible patients with atrial fibrillation who are at moderate to high
risk for stroke, particularly when well-organized management of anticoagulation
can be provided.32,47

REFERENCES

The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with
nonrheumatic atrial fibrillation. N Engl J Med.1990;323:1505-1511.PubMed

References

The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with
nonrheumatic atrial fibrillation. N Engl J Med.1990;323:1505-1511.PubMed

Letters

The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with
the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.

Return to: Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation: How Well Do Randomized Trials Translate Into Clinical Practice?

This feature is provided as a courtesy. By using it you agree that that you are requesting the material solely for personal, non-commercial use, and that it is subject to the AMA's Terms of Use. The information provided in order to email this article will not be shared, sold, traded, exchanged, or rented. Please refer to The JAMA Network's Privacy Policy for additional information.

Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.